Post-Chemotherapy ctDNA Status May Support Organ Preservation Decisions in Rectal Cancer

Detectable circulating tumor DNA (ctDNA) following neoadjuvant chemotherapy was associated with persistent disease and recommendation for total mesorectal excision (TME) in patients with T1-3, N0 low or mid rectal cancer, according to findings from a retrospective analysis of the phase 2 NEO/CCTG CO.28 trial (NCT03259035), which were presented at the 2025 Gastrointestinal Cancers Symposium.1

Among plasma samples collected from the 53 patients included in NEO, ctDNA of any stage was detected in 45.8% of pre-chemotherapy samples (n = 48) and 8.7% of post-chemotherapy samples (n = 46; P < .0001). ctDNA detection was significantly associated with T stage . When stratified by clinical stage, the respective rates of pre- and post-chemotherapy ctDNA detection were 14.3% and 12.5% for T1 disease (n = 15); 53.1% and 3.6% for T2 disease (n = 60); and 44.6% and 20.0% for T3 disease (n = 19).

Among patients with paired pre- and post-chemotherapy samples (n = 41), 48.8% remained ctDNA negative post-chemotherapy, 43.9% cleared ctDNA negativity or had decreased ctDNA levels post-chemotherapy, and 7.3% had increased ctDNA levels post-chemotherapy.

Furthermore, detection of ctDNA post-chemotherapy but prior to excision was associated with a recommendation for TME. In the pre-chemotherapy group, 38.5% of patients with no ctDNA detection (n = 26) and 50.0% of patients with ctDNA detection (n = 22) were recommended TME (P = .38). However, in the post-chemotherapy/pre-excision group, all patients with ctDNA detected (n = 4) were recommended for TME or had high-risk features upon excision and required a TME vs 38.1% of those with no ctDNA detection (n = 42; P= .03).

NEO Trial Background and ctDNA Analysis Rationale

The NEO trial investigated the efficacy of 3 months of neoadjuvant FOLFOX/CAPOX followed by endoscopic excision in 58 patients with T1-3, N0 low or mid rectal cancer. At the time of excision, patients with tumors without downstaging or those that did not have a pathologic complete response or downstaging to ypT1 disease (with good prognostic features) were recommended for TME. Among 23 patients who were recommended for TME, 13 declined and elected to proceed directly to observation, resulting in an overall organ preservation rate of 79% (90% CI, 69%-88%).2 The overall DFS rate was 84.3% (95% CI, 72.0%-91.5%).3

“There are limited data around the utility of ctDNA in this very early-stage population, however there are some other studies suggesting that it might be associated with response, as well as recurrence-free survival [RFS] in more advanced disease,” lead study author Jonathan M. Loree, MD, MS, FRCPC, BMSc, stated in a presentation of the data.1 Loree is a medical oncologist at BC Cancer, as well as an associate professor of medicine at The University of British Columbia in Vancouver, Canada.

In NEO, investigators collected and sequenced plasma samples across more than 20,000 epigenomic regions. Samples were acquired from patients prior to chemotherapy, after 3 months of chemotherapy but before excision, and every 12 months for 3 years during surveillance (12 months, n = 34; 24 months, n = 32; 36 months, n = 28). On-progression samples were also collected when available (n = 2). The samples were retrospectively analyzed with the tissue-free epigenomic Guardant Reveal assay.

Additional ctDNA Analysis Findings

At either time point, there was no association between ctDNA detection and RFS.

“This is likely because this is a very good prognostic group, and there were few recurrences in the study, as patients did very well with this [treatment] approach,” Loree said.

In the pre-chemotherapy group, the recurrence rates were 11.5% and 9.1% in patients with no ctDNA detection and ctDNA detection, respectively (P = 1). In the post-chemotherapy/pre-excision group, these respective rates were 9.5% and 25.0% (P = .38). At a median follow-up of 4.3 years, the 3-year RFS rate was 90.9% in patients with ctDNA detection pre-chemotherapy vs 88.5% in those without ctDNA detection at this time point (HR, 0.79; 95% CI, 0.13-4.75; P = .80). Furthermore, the 3-year RFS rates were 75.0% vs 90.5%, respectively, among patients with and without ctDNA detection post-chemotherapy/pre-excision (HR, 2.82; 95% CI, 0.31-25.29; P = .36).

Among patients with low recurrence risk, investigators did not observe false positives for ctDNA status. Five recurrences occurred on the study, 2 of which were local recurrences. One of those 2 patients had ctDNA-positive disease at the time of local recurrence.

“This is really important because it is a time point when we would want that extra decision aid,” Loree emphasized.

Limitations of this research include its small sample size and low relapse event rate, which created challenges when determining prognostic differences based on ctDNA detection. Moreover, plasma samples were only available once every 12 months during surveillance, and some patients were missing samples at surveillance time points. Loree explained that these limitations may have resulted in underestimating the sensitivity and lead time for recurrence prediction, which is important to consider for patients undergoing non-operative disease management.

“Further studies are warranted to see if [ctDNA] can be an additional [organ preservation] decision tool for patients and clinicians,” Loree concluded.

Disclosures: Dr Loree reports performing consulting or advisory roles with Advanced Accelerator Applications, Amgen, Bayer, Guardant Health, Ipsen, Merck, Roche, and Taiho Pharmaceutical; as well as receiving research funding from Ipsen (Inst.) and Personalis.

References

1. Loree J, Titmuss E, Brown C, et al. Tumour-free ctDNA detection as a decision tool to support organ preservation in node-negative rectal cancer undergoing neoadjuvant chemotherapy, excision, and observation in the phase II NEO trial (CCTG CO.28). J Clin Oncol. 2025;43(4):20. doi:10.1200/JCO.2025.43.4_suppl.20
2. Kennecke HF, O'Callaghan CJ, Loree JM, et al. Neoadjuvant chemotherapy, excision, and observation for early rectal cancer: the phase II NEO Trial (CCTG CO.28) Primary end point results. J Clin Oncol. 2023;41(2):233-242. doi:10.1200/JCO.22.00184
3. Brown CJ, O’Callaghan C, Loree JM, et al. Neoadjuvant chemotherapy, excision, and observation for early rectal cancer: the phase II NEO trial (CCTG CO.28) results after minimum 3 years follow up. Ann Oncol. 2024;35(2):S462-S463. doi:10.1016/j.annonc.2024.08.634